Shah Masaud, Ahmad Bilal, Choi Sangdun, Woo Hyun Goo
Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.
Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
Comput Struct Biotechnol J. 2020;18:3402-3414. doi: 10.1016/j.csbj.2020.11.002. Epub 2020 Nov 12.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is a novel beta coronavirus. SARS-CoV-2 uses spike glycoprotein to interact with host angiotensin-converting enzyme 2 (ACE2) and ensure cell recognition. High infectivity of SARS-CoV-2 raises questions on spike-ACE2 binding affinity and its neutralization by anti-SARS-CoV monoclonal antibodies (mAbs). Here, we observed Val-to-Lys417 mutation in the receptor-binding domains (RBD) of SARS-CoV-2, which established a Lys-Asp electrostatic interaction enhancing its ACE2-binding. Pro-to-Ala475 substitution and Gly482 insertion in the GSTPCNV-loop of RBD possibly hinders neutralization of SARS-CoV-2 by anti-SARS-CoV mAbs. In addition, we identified unique and structurally conserved conformational-epitopes on RBDs, which can be potential therapeutic targets. Collectively, we provide new insights into the mechanisms underlying the high infectivity of SARS-CoV-2 and development of effective neutralizing agents.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）可导致2019冠状病毒病（COVID-19），是一种新型β冠状病毒。SARS-CoV-2利用刺突糖蛋白与宿主血管紧张素转换酶2（ACE2）相互作用，以确保细胞识别。SARS-CoV-2的高传染性引发了关于刺突-ACE2结合亲和力及其被抗SARS-CoV单克隆抗体（mAb）中和的问题。在此，我们观察到SARS-CoV-2受体结合域（RBD）中发生了缬氨酸到赖氨酸417的突变，该突变建立了赖氨酸-天冬氨酸静电相互作用，增强了其与ACE2的结合。RBD的GSTPCNV环中脯氨酸到丙氨酸475的替换以及甘氨酸482的插入可能会阻碍抗SARS-CoV mAb对SARS-CoV-2的中和作用。此外，我们在RBD上鉴定出独特且结构保守的构象表位，它们可能成为潜在的治疗靶点。总体而言，我们为SARS-CoV-2高传染性的潜在机制以及有效中和剂的开发提供了新的见解。
